The prefrontal cortex (PFC) functions in an executive role to, in part, oversee activity within limbic reward regions, including the nucleus accumbens and ventral tegmental area (VTA). Research suggests that the use of drugs of abuse can produce a dysfunctional PFC leading to increased impulsivity, and thereby drug craving, which can then act as a switch from casual to compulsive drug use. Behavioral sensitization, which can serve as a model for drug-induced neuroplasticity, is the enhanced motor-stimulant response that occurs with repeated exposure to psychostimulants, such as cocaine. Previous studies have suggested that the ventromedial PFC (vmPFC) plays an important role in the development of sensitization. Specifically, recent studies demonstrated that repeated exposure to cocaine produces a transient attenuation in cocaine-induced dopamine release and a concomitant augmentation in glutamate release in the vmPFC. Furthermore, dopamine D2 receptor (D2R) function appears to be decreased in cocaine sensitized animals. These data support the hypothesis that sensitization is associated with changes in inhibitory and excitatory modulation of vmPFC pyramidal neurons that leads to an increase in excitatory transmission to the nucleus accumbens and ventral tegmental area; regions previously linked to sensitization. The present proposal will continue to study this hypothesis. Thus, Aim 1 will determine whether the apparent reduction in dopamine D2R function seen in sensitized animals is associated with a reduction in the ability of intra-vmPFC infusion of the D2 agonist quinpirole to reduce mesocorticolimbic glutamate transmission and mesoaccumbens dopamine transmission using in vivo microdialysis. Aim 2 will explore the involvement of Group I and Group II metabotropic glutamate receptors (mGluR) in sensitization. Studies in this aim will include intra-vmPFC injection of agonists or antagonists to mGluRs to determine their involvement in the initiation and expression of sensitization. Follow- up studies will determine whether the ability of the mGluRs to modulate mesocorticolimbic glutamate transmission and mesoaccumbens dopamine transmission is altered in sensitized animals. Aim 3 will determine whether repeated cocaine exposure influences the release of vesicular versus non-vesicular pools of glutamate in the vmPFC. Additional studies will determine whether D2R or mGluR regulation of glutamate release from vesicular and/or non-vesicular sources is altered in sensitized animals. Taken as a whole, the proposed studies should better define the mechanisms by which repeated cocaine alters vmPFC function, thereby leading to enhanced glutamate transmission in the VTA and nucleus accumbens that is associated with behavioral sensitization. Increased knowledge of drug-induced neuroplasticity in the vmPFC should lead to a better understanding of the mechanisms that underlie the switch from casual to compulsive drug use. Cocaine-induced behavioral sensitization has been proposed to be a useful model for drug-induced neuroplasticity. Understanding cocaine-induced neuroplasticity in the medial prefrontal cortex could help explain the mechanisms responsible for the switch from casual to compulsive drug use. Thus, the proposed studies are relevant in that an increased understanding of the mechanisms of sensitization might lead to improved treatment strategies for cocaine addiction.